REVIEW
Ecological Theories and Major Hypotheses in Ethnobotany:
Their Relevance for Ethnopharmacology and Pharmacognosy
in the Context of Historical Data
Marco Leonti1 &Laura Casu2 &Domingos Tabajara de Oliveira Martins3 &Eliana Rodrigues4 & Guillermo Benítez5
Received: 30 April 2020 / Accepted: 20 May 2020 # Sociedade Brasileira de Farmacognosia 2020 Abstract
The cross-cultural exchange of plant resources between societies across the globe added to the diversification of medicinal floras and pharmacopeias. Understanding how and why people select plants for medicine is still a common focus and topic addressed by the interdisciplinary research fields of ethnobotany, anthropology, ethnopharmacology, ethnomedicine, pharmacy, phytochemistry, and pharmacognosy. Here, we scrutinize recently reviewed ethnobotanical theories and hypotheses, which focus on the selection of plants as medicine by putting them into historical, ecological, and pharmacological perspective. We contextualize the availability, versatility, and diversification hypotheses, often presented in association with the inclusion of non-native species or imported herbal drugs into medicinal floras or ethnopharmacopeias. We also discuss the relevance of the concept of utilitarian redundancy and the apparency hypothesis, as well as the appropriateness of various statistical models applied for assessing non-random plant selection. It appears that the concept of utilitarian redundancy has been applied in a too reductionist and uncritical way, while the apparency theory is conceptually inconsistent and contradictive allowing for multiple interpretations. While the availability, versatility, and diversification hypotheses are not contextualized historically, they are used to explain retrospectively deliberate and well-documented human activities and cultural developments. Therefore, considering the cultural history and the pharmacology of plants is essential for the formulation of hypotheses related to the selection of plants as medicine and food. Ecological research questions applied to human-plant relationships should consider the historical impact of human culture as a framework and confounder to be integrated into the analysis.
Keywords Apparency theory . Diversification hypothesis . Non-random plant selection . Availability theory . Utilitarian redundancy . Versatility hypothesis
Introduction
Communication between cultures has ever since highlighted the importance of exchanging medical knowledge and effi-cacious materia medica. The basis of our current pharma-copeias and local herbal medicines (also popular or folk medicines, medicinal floras, and sometimes referred to as “ethnopharmacopeias” or “traditional pharmacopeias”) evolved along the same lines and principles until the offi-cial application of a “regulatory character” to pharmaco-peias came into place (Urdang 1951; Martins et al. 2019). Considering the rich body of literature about the historical development of materia medica (e.g., Tschirch 1910; Heffter 1914; Mann 1984; Balick and Cox 1996; Dal Cero et al. 2014, Rivera et al. 2017; Leonti and Verpoorte 2017; and references therein), it becomes clear that ethnobotanical studies did not start with the publication Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s43450-020-00074-w) contains supplementary material, which is available to authorized users.
* Marco Leonti
marcoleonti@netscape.net; mleonti@unica.it 1
Dipartimento di Scienze Biomediche, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy
2 Dipartimento di Scienze della Vita e dell’Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy
3
Departamento de Ciências Básicas em Saúde, Faculdade de Medicina, Universidade Federal de Mato Grosso, Cuiabá 78060-900, Brazil
4
Centro de Estudos Etnobotânicos e Etnofarmacológicos, Universidade Federal de São Paulo, Diadema, SP, Brazil 5 Departmento de Botánica, Universidad de Granada, Campus
Universitario de Cartuja s/n, 18071 Granada, Spain
https://doi.org/10.1007/s43450-020-00074-w
by Harshberger (1896:“The purpose of ethnobotany”) and that ethnopharmacological investigations did not begin with Efron et al. (1970:“Ethnopharmacologic search for psycho-active drugs”; see also Heinrich2014). The merits of these two publications were merely the introduction and diffusion of new terms, which were, however, describing already established scientific concepts and fields of research pur-sued in pharmacognosy, pharmacology, pharmacy, medi-cine, natural history, and cultural anthropology.
This review aims to bring the importance of the historical background of medicinal plant use and research to the fore-front and argues that only in the light of cultural history of plants (see, e.g., Bye1993; Balick and Cox1996; Prance and Nesbitt2005) does the interpretation of current plant use make sense (Leonti2011; Martins et al.2019). Valuable plants and their products have been deliberately exchanged across conti-nents at least since the beginning of the Neolithic age (Zohary and Hopf2000; Diamond2002; Prance and Nesbitt2005) while non-intentional exchange of plant germplasm seems to have accompanied human activity ever since (Willerding
1986). The detection of azulene and coumarin derivatives in the dental calculus of Neanderthal remains from Spain sug-gests that plants belonging to the Asteraceae were used for medical purposes already in the Middle Paleolithic (Hardy et al.2012).
“Plants have determined the very course of civilization. In the thirteenth century, Marco Polo described an island producing pepper [Piper nigrum L., Piperaceae; Fig. 1], nutmegs [Myristica fragrans Houtt., Myristicaceae], spikenard [Nardostachys jatamansi (D.Don) DC., Caprifoliaceae], galin-gale [Alpinia spp., Zingiberaceae], cubebs [Piper cubeba L.f., Piperaceae], and all the precious spices that can be found in the world. This report spurred a search for the Spice Islands, which inadvertently resulted in Europeans’ discovery of America and culminated in Magellan’s circumnavigation of the globe. Since the Renaissance, patterns of international trade in rubber [Hevea brasiliensis (Willd. ex A.Juss.) Müll.Arg. (Euphorbiaceae)], opi-um [which contains the analgesic alkaloid morphine (1) and the antitussive codeine (2) from Papaver somniferum L., Papaveraveae; Fig.2], and quinine [(3) from Cinchona spp.
(Rubiaceae; Fig.3) to treat malaria] have altered the fates of entire nations” (Balick and Cox1996).
Global geographical and biological predispositions, such as the extension of landmasses and the availability of species amenable to domestication, causally conditioned the inter-change and acceptance of knowledge, technology, and germ-plasm (Diamond 2005). Garlic (Allium sativum L., Amaryllidaceae), for instance, is thought to have its origin in a wild progenitor native to eastern Turkey, Iran, and central Asia (Zohary and Hopf2000). Following cultural exchange, garlic was gradually incorporated into diets and medicines and now is consumed as food and (preventive) medicine across the globe (Rivlin2001). Another example consists of a medicinal plant complex that has lost therapeutic importance in recent times including different Ipomoea species (Convolvulaceae) with cathartic, acrid-tasting, and resin-producing roots used by the Aztec and indigenous populations of Mexico for their purgative properties (Linajes et al. 1994; Pereda-Miranda et al. 2006). The roots known as“jalaps” were imported to Europe and used as substitutes for the Mediterranean scam-mony (Convolvulus scammonia L., Convolvulaceae; Fig.4) (Linajes et al. 1994; Pereda-Miranda et al. 2006). Ipomoea Fig. 1 Pepe (Piper nigrum L.) taken from Matthioli1568
purga L. was first introduced to botanical gardens in England, France, and Germany and later cultivated in Jamaica and India to satisfy the demand of Europe and North America (Linajes et al.1994; Pereda-Miranda et al. 2006).
From the perspective of causal historical developments, this article critically discusses some of the ecological theories and hypotheses currently pursued in ethnobotany (Gaoue et al.
2017). We focus on those hypotheses and theories related to plants used as medicines, discussing their relevance for ethnopharmacology and their coherence with cultural-historical and ecological facts and argue that (a) it is of basic importance to understand the historical background and de-velopment of plant use in order to contextualize specific the-ories and concepts about plant use in a meaningful way and (b) that for a meaningful formulation of ecological hypotheses applied to the selection of medicinal plants, hypotheses need to be contextualized by a multidisciplinary framework, re-specting the standards and knowledge of each of the disci-plines involved.
According to Gaoue et al. (2017) “The most promising hypothesis-driven approaches to date have come from testing whether patterns of human use of medicinal plants align with the predictions of the theoretical frameworks from ecology…[Moreover,] …it is important for ethnobotanists to recognize the breadth of current ethnobotanical theories and understand how these theories can be used to develop testable hypotheses”. We agree that theoretical ecological frameworks may contribute to our understanding of plant selection and use but consider them shortsighted regarding underlying historical and socio-cultural developments and, therefore, not sufficient Fig. 4 Scammonea (Convolvulus scammonia L.) from Matthioli1568
Fig. 3 Cinchona tree (Cinchona officinalis L.) cultivated at José Celestino Mutis botanical garden in Bogota, Colombia, August 19, 2016, Photo: G. Benítez
Fig. 2 Opium poppy (Papaver somniferum L.) in the wild, from ancient cultures. Granada Province, Spain, May 11, 2009. Photo: G. Benítez
for addressing human plant use, especially when applied exclu-sively. We also agree that“it is critical for emerging ethnobota-nists to be exposed to these theories in a systematic way” (Gaoue et al.2017) specifically, because one needs to have basic histor-ical background knowledge for understanding theories and hy-potheses and to judge whether they are meaningful and scientif-ically sound, outdated, or anachronistic (Anderson2017).
Theories, Hypotheses, and Main Criticisms
The hypotheses and theories focused on in this discussion and our main points of critique are:
(a) The utilitarian redundancy model, which “proposes that species that share the same therapeutic function (i.e., func-tional redundancy) are redundant and are predicted to ex-perience reduced use-impact as the use pressure is diffused across a greater number of species” (Albuquerque and de Oliveira2007; Gaoue et al.2017). Main criticism: we dis-cuss the relevance of the utilitarian redundancy theory of herbal medicines in the light of the genetic variability of humans compared to the species and drug-specific chemis-try of plant-based pharmacology and criticize the undiffer-entiated and reductionist concept of“therapeutic function,” which appears to be conceived as being diagnosis indepen-dent classifications into more or less finely tuned etic cate-gories of medical use without contemplating the pharma-cology or chemistry of the specific herbal drugs.
(b) The availability hypothesis, which according to Gaoue et al. (2017)“states that plants are used for medicine be-cause they are more accessible or locally abundant” (see also Albuquerque2006). Main criticism: it is rather intui-tive that resources need to be available in order to be used. We argue that instead of talking about an availability hy-pothesis for describing this circumstance, it would be more appropriate to build on the well-established law of demand and supply.
(c) The versatility hypothesis (Gaoue et al.2017), which sug-gests“that introduced plants are incorporated as medicine by way of experimentation with introduced food and orna-mental plants” (Bennett and Prance2000; Alencar et al.
2010). Main criticism: the way by which this hypothesis is applied ignores the fact that culturally important and already versatile plants were introduced to other places and cultures with the intent to diversify food and medicine and useful resources at large.
(d) The diversification hypothesis (Gaoue et al.2017), which “suggests that exotic plant species are selected to fill ther-apeutic vacancies in an ethnopharmacopoeia, perhaps due to novel bioactivity, thereby diversifying the set of treat-ment options” (Albuquerque2006; Alencar et al.2010,
2014). Main criticism: introduced dietary plant species of-ten had already established uses as medicines in their place
of origin. That profiles of secondary metabolites are the outcome of phylogenetic history reflecting ecological con-straints is accepted knowledge. Therefore, introduced spe-cies have a high probability of containing bioactive second-ary metabolites not found in local sources.
(e) The insect-plant coevolution related apparency theory defines“something bound to be found” as being “appar-ent” (“visible, plainly seen, conspicuous, palpable, obvi-ous” (Feeny1976)) and explains why short-lived, “non-apparent” species contain qualitative defense compounds “whereas species with long lifespans (apparent) face higher herbivore pressure and invest in more expensive quantitative defenses” (Feeny1976; Gaoue et al.2017). “Thus, non-apparent plants (short lived, herbaceous, ear-ly successional) are more likeear-ly to be used for medicine than “apparent” plants (perennial, woody, dominant plants)” (Gaoue et al.2017). Main criticism: we explain that Feeny’s concept of “apparency” is convoluted and the definition of apparency open to arbitrary interpreta-tion as Feeny also considered“apparency to mean ‘sus-ceptibility to discovery’ by whatever means…since ani-mals, fungi and pathogens may use means other than vision to locate their host-plants” (Feeny1976). We be-lieve that Feeny’s consideration of other senses besides vision being used by organisms to detect food (Feeny
1976) is compatible with reality but not reconcilable with the division into annuals and perennials or plants with qualitative and quantitative defense compounds. As an alternative and inclusive theory, explaining and synergizing with the observation that weeds and non-apparent species are frequently included in medicinal floras, we highlight the circumstance that the degree of geographical range size of a taxon correlates with the probability to be included in the medicinal flora at the local as well as the global level (Leonti et al.2013). (f) Finally, we discuss the epistemological appropriateness
of various statistical models applied for assessing non-random plant selection and to test for overused and un-derused plant taxa with respect to the overall available flora.
Discussion
Utilitarian Redundancy
Disease Classification
The concept of utilitarian redundancy proposes that different species, which“share the same therapeutic function (i.e., func-tional redundancy) are redundant” (Gaoue et al.2017, p. 278). Redundant species have initially been defined by
Albuquerque and Oliveira (2007, p. 158)“as those that share the same function in a given local medical system. Function is used to define the local therapeutic action category (e.g., stom-achaches, coughs, fever etc.” Studies using the concept of utilitarian redundancy, such as Alencar et al. (2014) or Santoro et al. (2015), do not specify which species are redun-dant and instead point out disease categories and body system disorders, which are considered more or less redundant based on the number of medicinal species with uses arranged into these categories.
Redundancy would thus depend on species richness per category of use. Depending on such reductionist approaches, ginger (Zingiber officinale Roscoe, Zingiberaceae), pepper (Piper spp., Piperaceae), and chili pepper (Capsicum spp., Solanaceae) would, for instance, turn out to be redundant for several uses considering the existing overlap (vide infra). Chemically, gingerol (4) is related to capsaicin (5) and piper-ine (6), the compounds which give ginger, chili peppers, and black pepper, respectively, their particular spiciness and make them“hot”. These compounds determine the therapeutic uses, which are often related to digestive problems due to their capacity to increase digestive fluids that can help speeding up the digestion process and relieve diarrhea.
Moreover, for identifying the redundancy of therapeutic functions, the multiple pharmacological mechanisms of action of herbal drugs as well as precise diagnoses, including the identification of pathogenic agents, physiological and histo-logical markers would be necessary. This would require
specific information about the network pharmacology of com-plex mixtures as well as diagnostic tools and techniques gen-erally not available in ethnomedical contexts, which is the reason why the International Classification of Diseases (ICD) cannot be used for classifying ethnomedical data.
Besides all this, the idea of redundancy also ignores the concept and existence of medicinal plant complexes including taxonomically unrelated assemblages of herbal drug species. Influenced by common key morphological and organoleptic features, such medicinal plant complexes share common names and therapeutic uses (Linares and Bye 1987) while their chemical content is dissimilar.
Polymorphism and Personalized Medicine
Due to inherent polymorphisms, not all individuals respond in the same way to xenobiotics. Genetic factors influence epide-miology (Khoury et al.1993), and the response of individuals towards herbal and pharmaceutical drugs is affected by poly-morphisms at different levels. This includes polypoly-morphisms of pharmacological targets, e.g., receptors; enzymes; the sys-tem responsible for detoxifying and metabolizing xenobiotics, e.g., efflux pumps; and the microbiome at large (Rizkallah et al.2010). Major components underlying differential drug metabolism and drug response are about 12 enzymes belong-ing to the cytochrome 450 (CYP) superfamily. Physiological, ontological, and genetic factors are responsible for the expres-sion of each CYP, and therefore, differences between popula-tions and individuals exist (Cambria-Kiely and Gandhi2002; Zanger and Schwab 2013; Lazalde-Ramos et al. 2014). Biomedicine, in fact, addresses polymorphisms in pursuing a pharmacogenomics approach considering individual differ-ences in pharmacokinetics (absorption, distribution, biotrans-formation, and excretion) and pharmacodynamics (dose-response relationships) with the aim of offering personalized drug treatment (Clayton et al.2006; Relling and Evans2015). The individual reaction to pharmaceutical drugs and the spe-cific and still often unknown chemical composition of herbal drugs (Evans 1998; Bent and Ko 2004; Heinrich 2010; Pferschy-Wenzig and Bauer2015) is the reason why the util-itarian redundancy hypothesis applied in such an undifferen-tiated way does not do justice to herbal medicine.
Knowing a range of different treatment options for appar-ently similar health problems moreover represents a rational strategy in herbal and traditional medicine and medicine at large (Porter and Kaplan2011): In case a specific remedy does not show the desired efficacy, along the trial-and-error ap-proach, alternative remedies can be sought. In popular medi-cine, such therapeutic alternatives are often subsumed under the same vernacular name and considered herbal drug com-plexes (Linares and Bye 1987; Estrada-Reyes et al.2004; Pardo-de-Santayana et al.2005; Obón et al.2012). Apart from the relevance of individual drug metabolism and response, it is
important for people living in biologically and ecologically diverse areas to recognize medicinal plants for the same health problem in each of the ecosystems used for their livelihood. Pharmaceutical Redundancy: Where This Concept Makes Sense
Generally, woody species (see also the apparency theory by Feeny1976) have the tendency to defend themselves from herbivory with polyphenolic anti-digestive metabolites. The widely spread tanninic and galloylated polyphenols interact with proteins through covalent bonding or hydrogen bridges and form protein-polyphenol complexes on the oral and vag-inal mucosa, gastrointestvag-inal lining, and cutaneous lesions (Wagner, et al.2007). The protein-polyphenol interaction is exploited by the tanning industry for the production of leather and in medicine for curing diarrhea, dysentery, and cutaneous and mucosal irritations and lesions. In herbal and traditional medicine, often tree barks (Quercus spp., Fagaceae, Hamamelis virginiana L., Hamamelidaceae, Psidium guajava L., Myrtaceae), the (un)-ripe fruits of chestnut (Castanea sativa Mill., Fagaceae), pomegranate peel (Punica granatum L., Lythraceae), bilberry (Vaccinium myrtillus L., Ericaceae), and tea leaves (Camellia sinensis (L.) Kuntze, Theaceae) are used interchangeably for these purposes. Kinos are tannin-rich wood exudates that can be obtained from a variety of species and genera (Locher and Currie2010). They are used for their styptic properties and were formerly also included in European pharmacopeias and used for treating diarrhea, dys-entery, hemorrhages, and cutaneous lesions (Locher and Currie2010). Although the specific compositions of phenolic constituents between different types of kinos differ, redundan-cy most probably exists. Other examples of herbal drugs with a certain degree of redundancy are those containing mucilage, alditols (e.g., xylitol (7), sorbitol (8), andD-mannitol (9)) and triacylglycerides applied as mild laxatives and sweeteners (Wagner et al. 20,807). Xylitol (E967) is present in, e.g., Brassica oleracea var. botrytis L., Brassicaceae, and fruits of Fragaria vesca L., Rubus idaeus L., and Prunus domestica L., all Rosaceae; sorbitol (E420) is present in fruits of Sorbus aucuparia L., Rosaceae, andD-mannitol (E421) is contained in manna obtained from Fraxinus ornus L., Oleaceae.
Triacylglycerides are present in a variety of seed and fruit oils such as olive oil (Olea europaea L., Oleaceae), peanut oil (Arachis hypogaea L., Fabaceae), and linseed oil (Linum
usitatissimum L., Linaceae) while mucilages are present in seeds of Plantago afra L., Plantago ovata Forssk., Plantaginaceae, and L. usitatissimum, for example. Also, lax-ative anthranoid-containing drugs such as leaves and fruits of Senna alexandrina Mill., Fabaceae, roots of Rheum palmatum L. and Rheum officinale Baill., Polygonaceae, cortex of Frangula alnus Mill. and Frangula purshiana (DC.) A. Gray ex J.G. Cooper, Rhamnaceae as well as the sap of Aloe spp., Asphodelaceae show some redundancy. Herbal drugs containing mucilage and used for oral and respiratory prob-lems (e.g., derived from Malvaceae and Cetraria islandica (L.) Ach., Parmeliaceae) show redundancy for their soothing quality (Bruneton 1999; Hänsel and Sticher 2007; Wagner et al. 2007). Sesquiterpene lactones are known at the same time for their anti-inflammatory, cytotoxic, and allergenic properties, owing their activity to theα-methylene-γ-lactone moiety, which is able to alkylate nucleophiles of biomolecules by a Michael-type addition, especially cysteine sulfhydryl res-idues of proteins in general and specifically pro-inflammatory nuclear factor-kappa B, leading to undesirable cytotoxicity (Siedle et al.2004). This is probably the reason why sesqui-terpene lactone-rich herbal drugs from Asteraceae are fre-quently used as topical anti-inflammatory drugs (Moujir et al.2020) and show a certain degree of redundancy. In the late 1970s, sesquiterpene lactones were excluded by the US National Cancer Institute for therapeutical use because their highly reactive groups were thought to interact with any thiol group. However, structure–activity relationship studies of parthenolide (10) from the shoots of feverfew (Tanacetum parthenium (L.) Sch.Bip., Asteraceae), demonstrated that the chemical diversity imposed by its stereochemistry and confor-mational changes, probably restrain from nonspecific attacks onto thiol groups. Derivatives, with better hydrophilicity and retaining their potency, have been developed by conjugate addition of aromatics, particularly a tyramine moiety, or ali-phatic amines to the a-methylene group. Among those prod-ucts is the aliphatic acyclic amine, dimethylamino-parthenolide with specificity towards crucial cancer signaling pathways (Ghantous et al.2013).
Although flavor properties are not identical, herbal drugs used as natural low caloric sweeteners may also show some degree of redundancy (Soejarto et al. 2019) as well as the essential oil obtained from anise (Pimpinella anisum L., Apiaceae), fennel (Foeniculum vulgare Mill., Apiaceae) and star anise, (Illicium verum Hook.f., Schisandraceae) fruits, all
three with a high content of E-anethole (11), also known as anise camphor, 80–95%, 80%, and 80–90%, respectively (Bruneton1999; Rocha et al.2016). Above all, does utilitarian redundancy exist in the case of generic drugs (Kesselheim et al.2008).
The Availability, Versatility, and Diversification
Hypotheses
The expected profit, benefit, and availability of any resource determines its demand and value. Culturally important and versatile plants as well as their products were deliberately exchanged for economic reasons with the intention of diver-sifying food, medicine, and agricultural crops but also for sheer curiosity and experimentation (Tschirch1910; Balick and Cox1996; Bennett and Prance 2000; Diamond 2005; Prance and Nesbitt2005; El-Gharbaoui et al.2017; Martins et al.2019). To describe this circumstance and the result of this well-known historical interchange, sometimes, the avail-ability, diversification, and versatility hypotheses are applied (Alencar et al.2010; Gaoue et al. 2017; Hart et al.2017). According to Gaoue et al. (2017),“The versatility, availabil-ity, and diversification hypotheses attempt to explain the in-creasing or disproportionately large number of exotic plants utilized in traditional medicine”.
The Idea of Availability
With regard to the availability theory (Goaue et al. 2017), it is quite obvious that a plant or herbal drug (or anything else) needs to be available in one way or another; other-wise, its application is not possible. The costs invested to obtain a certain herbal drug or remedy depends on the balance between supply and demand while the demand may be influenced by a range of parameters (Benítez et al.2016). Textual and archaeological evidence demon-strate that spices and herbal drugs were imported from Africa, Arabia, Central Asia, Himalaya, or the Indo-Malayan region integrating the European and Mediterranean materia medica with exotic drugs since 2000 years (Heffter1914; Miller1969; Mann1984; Touwaide and Appetiti2013; Van der Veen and Morales2015; Staub et al.2016; El-Gharbaoui et al.2017; Rivera et al.2017). When the availability of a product is strict-ly limited such as for example with exotic and rare species or when the collection of a crude drug is laborious, the expected benefits driving the demand have a more dramatic impact on the value chain (Lopes2019).
Looking back at the herbal drug trade in the Middle Ages, Tschirch (1910) distinguished three large economic regions: the Indian and Arabic Ocean, the Mediterranean Sea, and the North and Baltic Sea. The first was con-trolled by Alexandria (Egypt), the second by the Italian city states (Venice, Genoa, and Pisa), and the third by
Bruges (northwest Belgium) and Lübeck (northern Germany). In the thirteenth century, for example, 100 kg pepper (P. nigrum) did cost the equivalence of 481 M [Marks] in Marseille, 512 M in Lombardy, 620 M in the Champagne, and between 683 and 796 M in England. At t h e b e g i n n i n g o f t h e s i x t e e n t h c e n t u r y , g i n g e r ( Z . o f f i c i n a l e ) w a s t h r e e t i m e s a s e x p e n s i v e i n Alexandria compared to Calicut (Kozhikode, India), and incense (Boswellia sp., Burseraceae) did cost five times more in Alexandria compared to Mecca (Tschirch 1910). Instead of pursuing the vague idea of availability, it would be more rewarding to apply the concept of balance of supply and demand in accordance with economic sciences (Nicholson and Snyder 2007; Varian 2010). As a proxy for calculating the balance between supply and demand when sales figures are not available, one could correlate the number of communities making use of a specific bo-tanical drug and its general ecological abundance assessed by the number of Universal Transverse Mercator grids, or through citations in phytosociological inventories (Pardo-de-Santayana et al. 2017). The availability and cultural valuation of a product influence its use, expenditure, and price following economic concepts and the availability theory is already reflected in the well-established econom-ic law of balance and supply.
The Idea and Concept of Versatility and Diversification The versatility hypothesis proposes that by way of experimen-tation, introduced plant species as food and ornamentals (Bennett and Prance2000) account with a higher diversity of medical uses than native species (Gaoue et al.2017). The diversification hypothesis proposes that introduced species with their novel chemistry and pharmacology may diversify the options of medical treatments (Alencar et al.2010; Gaoue et al.2017).“The diversification hypothesis suggests that ex-otic plant species are selected to fill therapeutic vacancies in an ethnopharmacopoeia, perhaps due to novel bioactivity, thereby diversifying the set of treatment options” (Albuquerque2006; Alencar et al.2010,2014; Gaoue et al.
2017).
The idea of versatility was presented by Bennett and Prance (2000, p. 91) who argued that from their compilation of 216 introduced species medicinally used in South America, 88 “were originally introduced as foods” and that “only 14 spe-cies likely were introduced for their therapeutic value.” Bennett and Prance (2000) made this assessment without showing any historical data that would sustain their claim and did not specify which species they were alluding to. As it turns out, however, most of the 216 species listed are used as medicines in their place of cultural origin (Europe and Africa) since thousands of years, which is in agreement with the no-tion that food is used as medicine and vice versa in the Old
World. Compare the 216 species with, for instance, the chapters in Matthioli (1568) or Avicenna (1998,2014) and seeSupplementary Material Bfor 106 chapters about species and genera in Matthioli’s (1568) translation of Dioscorides’
De Materia Medica (DMM) overlapping with the plant list in Bennett and Prance (2000). Cultural plants are often used for multiple purposes. Therefore, the most versatile species are the most likely to be interchanged exactly as a function of these multiple reasons.
The cultural perspective on versatility and diversification can be examined by means of the spice trade, which offers a historical and practical perspective for understanding the mechanism of inclusion of exotic drugs into local cuisine, pharmacopeias, and medical floras. The high content in fra-grant essential oil and the presence of secondary metabolites with antimicrobial properties render spices versatile and mul-tipurpose herbal drugs. They are used in medicine, in perfum-ery, as incense, and to conserve food, and they have been used in embalming practices and for making decaying food more palatable (Sherman and Billing 1999; Prance 2005; Papageorgopoulou et al.2009). Each odor, taste, and flavor is associated with a specific chemical profile able to transmit nutritional and pharmacological cues to varying degrees (Goff and Klee2006; Chaudhari and Roper2010; Breslin 2013). The fact that fragrant plant parts such as spices were ex-changed between cultures implies that the associated chemosensory qualities were not found among the local floral resources. This circumstance can be appreciated by contem-plating the collection of spices in our kitchens.
Under alien ecological conditions, exotic food species and spices are mostly dependent on horticulture and agriculture and are thus readily available for further experimentations (Johns1990; Harlan1992; Etkin2006). For culturally accept-ed plants and herbal drugs with already establishaccept-ed uses, ac-cidental, experimental, or post-prandial observations can oc-cur more easily, especially as food items are often ingested in considerable amounts. This intimate relationship has thus the potential to lead to new therapeutic uses.
Chemical and Pharmacological Perspectives on Versatility and Diversification
Fruits of black and the infructescences of long pepper (P. nigrum and P. longum L.), for instance, are important Ayurvedic herbal drugs used since ancient times for digestive problems, to stimulate appetite, and to increase peristalsis and the flow of saliva, as well as for pain relief, rheumatism, in-creased blood circulation, and treatment of fever and cold (Meghwal and Goswami2013). Black pepper is also used in perfumery and to preserve food (Srinivasan 2007). Dioscorides’ DMM testified the importance of pepper fruits as medicine in the Roman Empire during the first century of the current era (CE). Matthioli’s (1568) translation of DMM
mentions the promotion of appetite and digestion, induction of labor, the use as an analgesic, for treating disorders of the respiratory tract (angina [tonsillitis], cough, purge phlegm from the head), in ophthalmology, for contraception, treat-ment of swelling of glands, vitiligo, snake bites, and the im-portance and pepper fruits as an antidote in general. Similarly, Ibn al-Baytar (thirteenth century CE) described the impor-tance of black pepper in Arabic medicine for problems of the gallbladder, stomach, liver, teeth, circulatory system, and skin as well as nervous disorders (Leclerc1877–1883). The
flavor of pepper is determined mainly by the hot piperine (6) and volatile terpenes such as germacrene D, limonene,α and β-pinene, β-caryophyllene (12), and α-phellandrene (Jirovetz et al.2002). The global use and commercial value of pepper species have motivated scores of pharmacological studies, which became the basis for new therapeutic applications aug-menting the versatility of pepper. The hot taste of pepper fruits results from an interaction of the main alkaloid piperine with heat- and acid-sensitive transient receptor potential cation channels (TRPVs), which induce sweating and enhance the release of saliva and gastric juices. Piperine has shown a range of other biological properties including antimicrobial effects and the capacity to enhance metabolism in general (Srinivasan
2007; Meghwal and Goswami 2013; Butt et al. 2013). Piperine is currently exploited for improving the poor bio-availability of other drugs such as curcumine as well as a fat burner due to its metabolism-enhancing property (Shoba et al.
1998; Srinivasan2007; Meghwal and Goswami2013).
Moreover, fruits of P. nigrum and P. longum, as well as those of other Piper species, contain N-isobutylamide guineensine (up to 0.5%), which inhibits the cellular uptake of endocannabinoids (EC50= 290 nM; Nicolussi et al.2014). Guineensine (13) showed dose-dependent and significant anti-inflammatory and anti-nociceptive effects in a mouse model when given i.p. (Reynoso-Moreno et al.2017). Also, β-caryophyllene (BCP; 12), a ubiquitous sesquiterpene, for which pepper fruits are one of the major dietary sources, in-teracts with the endocannabinoid system. By acting selective-ly and as a functional agonist to the CB2 receptor (Ki of 155 nM), BCP contributes to the anti-inflammatory effects of pepper (Gertsch et al.2008). Also, gingerols and shogaols, the arylalkanones present in ginger, mediate their pungency via TRPV receptors. In addition, the flavor of ginger is deter-mined by its essential oil content, which is dominated by the
presence of sesquiterpenes such as (−)-zingiberene (14) and (+)-ar-curcumene (15) and characterized by the presence by zingiberol (mixture of cis- and trans-β-eudesmol) and citral (mixture of the isomers geranial and neral; Wichtl2002). Besides being used as a spice and food ingredient, ginger has become a globally used botanical drug available in a range of galenic forms and used to treat rheumatoid arthritis,
head-ache and migraine, digestive disorders, nausea related to preg-nancy, and motion sickness as well as upper respiratory tract infections (Barnes et al. 2002; Williamson 2002; Wichtl
2002). Similar to pepper also ginger was imported to the Roman Empire as a condiment and used for medicinal pur-poses such as for improving digestion and eyesight as well as an antidote (Matthioli1568).
Extracts and pure compounds derived from ginger have shown a range of anti-inflammatory mechanisms and effects in vitro and in vivo as well as in clinical studies (Barnes et al.
2002; Nievergelt et al. 2011). Gingerols, shogaols, and gingerdiones have also been found to interact with the human serotonin 5-HT1Areceptor in vitro with a Kibetween 3 and 20μM providing an explanation for the anti-emetic and pos-sibly mood-modulating effects of ginger products (Nievergelt et al.2010).
The most potent activator of TRPV1 is capsaicin (5), the pungent and hot principle of chili peppers being about 100 times more potent than piperine (Lawless and Heymann
2010). Similar to pepper and ginger, also hot chili peppers (Capsicum spp.; Fig.5) are used to flavor dishes and applied in traditional medicine and phytotherapy around the world. Capsicum species are used for their stimulant, antispasmodic, carminative, diaphoretic, counterirritant, and antiseptic prop-erties while capsaicin preparations are topically applied as rubifacients and to treat rheumatism, arthritis, and neuralgia (Barnes et al.2002; Wichtl2002).
The examples of pepper, ginger, and chili pepper showcase how a wider cultural diffusion of herbal drugs (availability) will lead to the establishment of new local uses (augmented versa-tility) and, as a feedback thereof, attract more toxicological and pharmacological studies. These three spices share several uses and properties and, not by chance, they are presented in se-quencing chapters in Matthioli (1568: Chapters 148 and 149, pp. 605–614). According to the utilitarian redundancy model by Albuquerque and Oliveira (2007), the uses of the three drugs
would be redundant for rheumatism and analgesics but the phy-tochemical and pharmacological data reviewed here disprove this at the molecular level. Notwithstanding all three spices are used for similar therapeutic categories and all interact with TRPVs, piperine, guineensine, capsaicine, gingerols, and shogaols all have a unique profile of molecular interactions and pharmacological properties.
Ecological Perspective on Versatility and Diversification The evolutionary and ecological history of plants determines allelochemistry and secondary metabolites, which can be used for assessing taxonomic relationships (“chemotaxonomy”; Wink2003). Although chemical and consequently pharmaco-logical convergence exist, e.g., nicotine, polyacetylenes, pu-rine alkaloids (Dewick2002; Wink 2003), it is well accepted in plant sciences that phylogenetically distant taxa and those which evolved under different ecological constraints reflect evolutionary history through disparate chemical profiles and, consequently, through different pharmacological properties (Wink and Waterman1998; Wink2003). In fact, the concept of chemotaxonomy (chemosystematics) has a long history (De Candolle1804; Hegnauer1962–1996) and can inversely
be used as a tool in the search for alternative drug sources in closely related taxa (Ge et al.2008; Pellicer et al.2018).
Main Criticism of the Versatility and Diversification Hypothesis
The several studies highlighted here and in Gaoue et al. (2017) present the versatility and diversification hypothesis uncoupled from causal historical, bio-cultural, pharmacological, and eco-logical backgrounds. Ecoeco-logical connections between plant phylogeny and allelopathy are not considered either. Those studies dealing with the versatility hypothesis do not contextu-alize the versatility of introduced species with the versatile uses these species experience in the geographical regions of origin (Martins et al.2019). It is also worth considering that the idea or concept of availability, versatility, and diversification are all interconnected. Conclusively, the power of each of these con-ceptual factors for assessing plant selection would be difficult to estimate as they are intrinsically and historically tied.
Apparency Theory
Feeny’s apparency theory is a thumb rule based on observations of insect-plant interactions and the more frequent presence of qualitative defense compounds (e.g., alkaloids, sesquiterpene lactones, inter alia) in short-lived, herbaceous species, consid-ered“non-apparent” and the accentuated presence of quantita-tive defense compounds (tannins, lignins) in woody perennials, which are classified as“apparent” (Feeny1976). Feeny (1976) defined apparent as“something bound to be found” as being “visible, plainly seen, conspicuous, palpable, obvious” (Feeny
1976) and unapparent as the contrary of this. Moreover, Feeny (1976) considered also abundance as a factor for apparency as well as the factors involved with the need of flowering plants to attract pollinators—and in case producing endochorous fruits— also frugivors. Finally, Feeny (1976) meant apparency to in-clude also“susceptibility to discovery” by whatever means… “since animals, fungi and pathogens may use means other than
vision to locate their host-plants.” With such a definition, every-thing is potentially apparent independent of its lifecycle and life form and renders the concept of the apparency theory arbitrary, confusing, and open to interpretations. As a consequence, the division into species with qualitative (non-apparent) and quan-titative (apparent) defense compounds would have no more rel-evance. Not surprisingly, testing the apparency hypothesis across medicinal floras derived from more primary and more disturbed ecological systems, or biomes with a marked season-ality, resulted in mixed results (Albuquerque2006; Ribeiro et al. 2014; Gaoue et al. 2017). Knowledge not considered by the apparency hypothesis is that herbaceous plant taxa have wider-ranging geographical distributions compared to that of woody taxa, which are more restricted to the species-rich tropical lati-tudes and that northern-hemispheric plant taxa have wider eco-logical amplitudes tending more towards woodyness compared to neotropical taxa (Hawkins et al.2011).
Several studies highlighted the overrepresentation of weedy species in medicinal floras of peoples living in environments disturbed by human activity (Stepp and Moerman 2001; Voeks2004; Leonti et al.2013). The selection of invasive spe-cies for medicinal purposes is a function of human activity and globalization. Weeds grow successfully in disturbed habitats, frequently contain qualitative defense compounds, are often her-baceous, and would thus, according to the apparency hypothe-sis, be“non-apparent.” Stepp (2004) pointed out that weeds are a rich source of pharmaceuticals and, therefore, suggested to screen this group of taxa for new medicinal compounds. However, how can it be that plants that are said to be non-apparent and hard to detect are overrepresented in medicinal floras? Whether something is apparent depends on the context, such as the type of ecosystem and specific herbivore-plant inter-action. Apparency evidently lies in the senses of the beholder: whether it is subterranean truffle (fruiting body, Tuber sp.), cab-bage (leaves, Brassica spp.), kawa-kawa (root; Piper methysticum G. Forst.), or tea (leaves; C. sinensis), the factors which attract or repel humans and other herbivores are the par-ticular organoleptic, chemosensory, nutritional, and pharmaco-logical properties and not their life form or life cycle. For in-stance, Brassicaceae metabolites, e.g., glucosinolates, serve as feeding cues for Pieridae caterpillars, and make Brassicaceae species apparent, i.e. detectable to these herbivore insects but are considered non-apparent (“hard to find”) by Feeny (1976). Therefore, it is not true that herbivores attack the most apparent or abundant species (Gaoue et al. 2017) as many herbivores, especially insects, are adapted to specific chemical marker com-pounds for identifying their diet (Kessler and Baldwin2002) whether the associated taxa is abundant, apparent or not.
What remains is the fact that many woody taxa use quantita-tive defense compounds while annual and weedy taxa usually rely on qualitative defense compounds. This does, however, not exclude the presence of tannins in herbaceous and short-lived plants (e.g., Potentilla spp., Rosaceae) or qualitative defense
compounds in woody perennials (e.g., quinine (3) in Cinchona spp., caffeine (16) in C. sinensis or Cola spp., (Malvaceae)). Moreover, Fabaceae (4th largest plant family), whether peren-nials or woody, have their own endogenous nitrogen source due to the activity of symbiotic nitrobacteria and are capable of pro-ducing qualitative nitrogen-containing defense compounds. The analysis of the life forms of the 225 taxa used for FDA approved or clinical trial drugs (Zhu et al.2011) showed that around half (98) derive from shrubby or woody taxa exploited above all for the presence of qualitative defense compounds; for example, see TableA, Supplementary Material and the supplementary file associated with Zhu et al. (2011). A comparison of the 63 drug and clinical trial-drug productive angiosperm and gymnosperm families censed by Zhu et al. (2011) with the overall 457 angio-sperm and gymnoangio-sperm families revealed that the 63 drug-producing families comprise around half of all species worldwide overlapping with major weed taxa and those used in rural me-dicinal floras (Leonti et al.2013). It has been suggested that this is related to“a broader range of ecologically-relevant information encoded in their genes with respect to locally occurring taxa” (Leonti et al.2013). This theory entails that the synthesis of allelochemicals in species-rich and widespread taxa is driven by a broader range of ecologically relevant information leading to metabolites with wider biological interactions than in more locally evolved taxa. The theory of geographical range size as a dependent factor is compatible with both observations: that of the inclusion of weeds and that of non-apparent species in medicinal floras. Moreover, this theory does not depend on more or less arbitrary definitions of apparency and the question what consti-tutes a weed but is based on molecular data representing phylo-genetic relatedness together as well as biogeography.
For testing the apparency hypothesis in a rigorous way, the composition and accessibility of the overall flora would need to be compared with that of the medicinal flora. The result would always either highlight the overproportional use of weedy and annual species (non-apparent) and underrepresen-tation of woody and apparent species or vice versa. But what would this tell us? What would be the relevance for ethnopharmacology or pharmacognosy? The outcome ulti-mately depends on the degree of ecological integrity, global-ization, and acculturation and whether the focus is on the northern or southern hemispheric realm. Instead of simply focusing on weedy species for drug discovery (Stepp2004), it might be more rewarding to focus the attention on wide-spread and species-rich plant taxa (Leonti et al.2013).
Theory of Non-random Plant Selection
The large cultural diversity expressed by human societies comes along with a relatively homogenous human genome (Pagel and Mace2004) and human societies show common needs and cravings for macro- and micronutrients and stimulants as well as therapeutics. For example, stimulating herbal drugs
containing the purine alkaloids, caffeine (16), theophylline (17), and theobromine (18) functioning as antagonists of the adenosine receptor, such as coffee (Coffea spp., Rubiaceae), cacao (Theobroma cacao L., Malvaceae; Fig.6), tea (Camellia sinensis (L.) Kuntze, Theaceae), guarana (Paulinia cupana Kunth., Sapinadaceae), mate (Ilex paraguariensis A.St.-Hil., Aquifoliaceae), and cola (Cola spp.) have been selected inde-pendently by human cultures residing on different continents (Heffter 1914; Weckerle et al.2010).
The use of purgative Convolvulaceae roots is known from pre-Hispanic Mexico (Linajes et al.1994), Brazil (Lira-Ricárdez et al. 2019), and Europe (Castañeda-Gómez and Pereda-Miranda2011), and similarly, the use of laxative anthranoids containing drugs such as the dried sap of Aloe spp., the roots of Rheum spp., fruit and bark of Rhamnus spp., and fruits and
Fig. 6 Cacao pods and beans (Theobroma cacao L.) from cultivated trees near Basupú, Bioko Island, Equatorial Guinea, May 20, 2015. Photo: G. Benítez
leaves of Senna spp. are reported from different time periods and continents (van Gorkom et al.1999; Heinrich et al.2004). In the same way, closely related phloroglucinol derivatives are the pharmacologically active principles of different anthelmintic drugs: Dryopteris filix-mas (L.) Schott, Dryopteridaceae, used to treat tapeworm infection in the Old World and Dryopteris athamantica (Kunze) Kuntze, Dryopteridaceae,“uncomocomo” in South Africa used for the same purpose; the kosso-flowers of Hagenia abyssinica (Bruce ex Steud.) J.F.Gmel., Rosaceae, used in Abyssinia for getting rid of intestinal parasites in general as well as“kamala” obtained from Mallotus philippensis (Lam.) Muell.Arg., Euphorbiaceae. This cross-cultural selection of bo-tanical drugs containing anthelmintic phloroglucinols bears ev-idence for the observatory skills of human societies when it comes to the selection of efficacious remedies (Heffter 1914).
In order to counter the argument put forward by some med-ical scholars that plant selection for therapeutic use would be guided by placebo effects alone, Moerman (1979) postulated that in such a case plant selection would be taxonomically ran-dom (Moerman1979). However, this would not necessarily be so because morphological and other organoleptic properties are culturally molded into symbolic interpretations along the doc-trine of signatures and act as a mnemonic aid, which can also help to transmit placebo effects (Etkin1988; Casagrande2000; Leonti et al.2002) or a “meaning response” (Moerman and Jonas2002). Since morphological and organoleptic properties show a non-random phylogenetic distribution, non-random dis-tribution is not necessarily an indicator for inherent pharmaco-therapeutic properties of botanical drugs and can lead to multiple and disparate therapeutic applications between individuals and cultures (Shepard2004; Leonti2011).
What Moerman’s approach did show is that certain fami-lies are overrepresented (and others underrepresented) in terms of number of species in indigenous medicinal floras when compared to the overall available flora of a specific region (Moerman et al.1999). The question of over and un-derrepresented plant families in medicinal florae was approached with different statistical methodologies sparking a scientific debate (Leonti et al.2012; Moerman 2012). Bennett and Husby (2008) suggested to use a binomial model instead of the linear regression model initially introduced by Moerman (1979). However, both the binomial and the linear regression model use percentage values for estimating the true proportion of averagely used species per family as if both, the plants used as medicine and the overall flora were assessed by a census. Since medicinal plant use is never assessed by a census but by means of samples, Weckerle et al. (2011) intro-duced a Bayesian approach, which takes the uncertainty around the true proportion of plants used as medicine into account. Since, however, also floral checklists are never complete and generally not congruent with the living space of human populations Weckerle et al. (2012) proposed an imprecise probability approach, which additionally considers
the uncertainty around the overall flora and, therefore, reflects the ecological realty more accurately.
Conclusions
Literature about the medicinal use of herbal drugs has been continuously published over the past 2000 years. Studies about the selection and inclusion of herbal drugs into medicinal floras and pharmacopeias have been con-ducted from various perspectives. The recent call for more hypothesis-driven research in ethnobotany resulted in an uncritical and sometimes erratic application of hypotheses also used for describing well-accepted knowledge and cultural realities. Since the hypotheses and theories discussed herein ignore the cultural history that guided and shaped human-plant interactions, we highlight its im-portance. Cultural history of plants contains causal cues and rationales for plant selection and the transmission of associated knowledge. Plants were selected for food and m e d i c i n e d u e t o t h e i r p a r t i c u l a r o r g a n o l e p t i c , chemosensory, nutritional, and pharmacological proper-ties. Plants and their uses have often been intentionally introduced to other regions of the world in relation to their dietary and medicinal qualities adding to the diver-sification of local medicinal floras and pharmacopeias. This resulted in an increased versatility of specific drugs. The often-perceived higher versatility of exotic species is a consequence of the simple fact that the most valuable, effective, and versatile species are the most likely to be cross-culturally exchanged. This constitutes a positive ef-fect of globalization.
Many more hypotheses related to the selection of plants used as medicine than the ones focused on here do exist. Interdisciplinary approaches including medicine, epidemiology, pharmacy, pharmacognosy, pharmacology, anthropology, botany, ecology and history have the highest potential to result in equilibrated appraisals and power to tackle relevant and new research questions. Therefore, identifying gaps in knowledge, which can be addressed with intelligent hypotheses, whether including concepts from ecology or not is not trivial. It requires comprehensive knowledge of the specific research situa-tion and its historical context in order not to oversimplify the inherent complexity of human-plant relationships. Ecological research questions applied to human-plant re-lationships should thus always consider the historical im-pact of human culture as a backdrop and confounder and integrate this parameter into the model and analysis. Acknowledgments We would like to thank Caroline Weckerle and Franz Huber for critical commentaries on a draft version of this paper.
Availability of Data and Material All data submitted incl. supplementa-ry material.
Code Availability Not applicable
Authors’ Contributions ML designed the review. LC, DTOM, ER, GB, and ML wrote the paper.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflicts of interest.
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